Method of lithiating five membered heterocycles

ABSTRACT

The invention relates to a method of lithiating CH-acidic five-membered heterocycles whereby the five-membered heterocycle is reacted with metallic lithium in an ether-containing solvent in the presence of an H acceptor.

This application is a 371 of PCT/EP99/07985, Oct. 21, 1999.

This invention relates to a method of lithiating CH-acidic five-memberedheterocycles, wherein the five-membered heterocycle is reacted withmetallic lithium in an ether-containing solvent in the presence of an Hacceptor. The invention also relates to a use of the products of themethod.

Hydrocarbons are more readily metalated the higher their CH-acidity, themore electropositive the metal, the larger the active surface area ofthe metal and the more polar the solvent. In this way alkynes,cyclopentadiene (and derivatives) and, for example, triphenylmethane canbe deprotonated by means of alkali metals. The problem, however, is thatsecondary reactions such as, for example, hydrogenations and/orCC-splitting, lead to poor yields. These secondary reactions becomeprominent particularly in highly polar solvents (for example,hexamethylphosphorous triamide (HMPT), 1,2-dimethoxyethane (1,2-DME)) orprotic solvents (for example, NH₃) . On the other hand, in solventswhich are not highly polar (for example, benzine, ether), the reactionrate is too-low to enable the direct metalation principle to be widelyutilised. Thus, for example, the metalation of triphenylmethane withpotassium in boiling 1,2-DME requires 10 hours. Caesium is a specialcase since, for example, it reacts quantitatively with toluene atrelatively elevated temperatures to form insoluble benzylcaesium.

Five-membered heterocycles have a considerably lower CH-acidity than doalkynes and cyclopentadienyls and are therefore harder to metalate. Thusfuran yields only small quantities of furan-2-carboxylic acid followingreaction with potassium or K/Na alloy and subsequent derivatisation withCO₂. Thionaphthene which has been activated by benzoanellation reactswith Na and, after reaction with CO₂ and H₂O, produces thederivatisation product in moderate yield:

It may be assumed that the poor yields are the result of double-bondhydrogenation.

Thiophene itself reacts with a lithium metal dispersion in THF only veryslowly and with moderate yields. After a reaction time of one week, aconversion of only 12% was observed by von Screttas (C. G. Screttas, J.C. S. Perkin Transactions II, 1974, 745-748, XP002102778).

The same article reports reactions of lithium with thiophene to formthienyllithium in the presence of various arenes such as, for example,naphthalene and/or α-methylstyrene. Thus at least 2 mol lithium wasrequired for the preparation of 1 mol thienyllithium in the presence ofan approximately stoichiometric quantity of naphthalene. The remaininglithium, or lithium dihydronaphthalenide, was used up by secondaryreactions. In Example 3 of the cited literature reference (p. 748), themetalation was carried out in the presence of a large excess ofthiophene. The yield of thienyllithium was 41% based on lithium used andless than 20% based on thiophene used.

The reaction of preformed lithium dihydronaphthalenide with excessthiophene (Example 4, p. 748) likewise resulted in poor product yields:52% based on the lithium reagent and 8% based on thiophene. The productyield in the reaction of lithium dihydronaphthalenide with thiophenecould be improved by admixing certain hydrocarbons such as1,1-diphenylethylene or α-methylstyrene. In Example 5 (p. 748) the yieldbased on the lithium reagent was 95%, a distinct increase. However, alarge excess (300% to 500%) of thiophene was used and consequently themetalation yields based on thiophene were below 50%. The molar quantityof the auxiliary reagent diphenylethylene or α-methylstyrene alsoexceeded the quantity of lithium or of lithium naphthalenide by a factorof at least 1.5.

The disadvantages of the syntheses described by von Screttas are ingeneral the extremely poor to moderate yields based on the lithiumreagent and/or, in particular, based on thiophene. Moreover, thereactions with lithium dihydronaphthalenide are two-step syntheses inwhich, in the first step, it is necessary to prepare the unstable andnot easily handled lithium dihydronaphthalenide which, in a second step,is reacted with thiophene. In all the cases described, large quantitiesof useless secondary products, namely naphthalene and, optionally,decomposition products are formed in the reactions.

The secondary reactions and unwanted secondary products observed whenmetals are used can be avoided if organometallic compounds such asbutyllithium are used as metalating reagents. However, butyllithium andother lithium organyls prepared from alkyl halides or aryl halides havethe disadvantage that ultimately only 50% at most of the metal employedfor their synthesis can be used for the 5-ring metalation, because intheir synthesis according to the equation

R—Hal+2Li→R—Li+LiHal↓

R=alkyl, aryl; Hal=Cl, Br, I

50% of the costly metal is converted into a salt of inferior value(LiHal). They are consequently expensive.

Of particular interest are organolithium syntheses which utilise thelithium as quantitatively as possible and, in a one-step reaction, alsoallow the best possible yields based on the organic substrate, in thiscase five-membered heterocycles. Metalated five-membered heterocyclesare used very frequently in organic synthesis, as they are indispensablefor the synthesis of valuable pharmaceuticals and plant protectionproducts.

The object of the invention is to eliminate the disadvantages of theprior art and to provide a method which, starting from metallic lithium,permits the. direct, i.e. one-step, lithiation of CH-acidicfive-membered heterocycles with high yields (for example, 70% and more)and makes it possible for the introduced metal to be utilised asquantitatively as possible for the deprotonation, without the formationof useless secondary products such as, for example, alkali halides.Moreover, the process is to proceed selectively, i.e. only certain CHfunctions of the heterocycle are to be metalated and there is to be nohydrogenation of the C═C double bonds present in the heterocycle.

This object is achieved by the method given in claims 1 and 2. Claims 3to 13 give further particulars of the given method. Claims 14 and 15give a particularly advantageous use of the compounds produced by themethod according to the invention.

In order to lithiate CH-acidic five-membered heterocycles having apK_(a) value of 30 to 40, the five-membered heterocycle is reacted withmetallic lithium in an ether-containing solvent in the presence of ahydrogen acceptor (H acceptor).

The method according to the invention proceeds from the method given inDE 19725192, in which the direct metalation of CH-acidic compoundscontaining one or more CH structural elements having pK_(a) values ofbetween 10 and 30 is described. Surprisingly, it has now been found thatconsiderably less acidic electron-rich five-membered heterocycles havinga pK_(a) value of >30 can also be metalated with a good yield through asuitable choice of the reactants and of the reaction conditions. It hasfurther been found that where the hydrogen acceptors according to theinvention are used, the product yields of >50% up to nearly 100% aredistinctly higher than the 41% obtained with the use of naphthalene orlithium naphthalenide.

The CH-acidic five-membered heterocycles used are compounds whichcontain as ring members, in addition to at least one acidic CH group, amaximum of 4 hetero elements selected from O, S, N and Se. These arefive-membered heterocycles containing one hetero atom such as e.g.

five-membered heterocycles containing two hetero atoms such as e.g.

five-membered heterocycles containing three hetero atoms such as e.g.

or five-membered heterocycles containing four hetero atoms such as e.g.

wherein R=H, alkyl, aryl,

All the above compounds can also be partially substituted, except thosespecies which, apart from the CH-acidic hydrogen atom, do not containany other hydrogen atom in the five-membered ring.

Particularly suitable CH-acidic five-membered heterocycles are those5-membered ring systems which have at least one olefinic CH group in thea-position to a hetero atom, selected from O, S, N, Se. Here the C atomof the CH-acidic group is sp²-hybridised.

The CH acidity of the five-membered heterocycles has a pK_(a) valuepreferably of about 30 to 40. Some data are shown in the Table below.

TABLE 1 CH acidities pK_(a) values in Compound cyclohexylamine Benzene43 (for comparison)

X = S X = O X = N—Me 38.4 38.1 ca.: 38-40

X = S X = O 37.1 36.8

29.5

28.1

In the reaction according to the invention, a hydrogen atom of theacidic five-membered heterocycle is exchanged for a lithium atom. Thereleased hydrogen is taken up by a suitable H acceptor. At the same timethe singly hydrogenated monomer and/or the hydrodimerisation product areformed as well as, to a lesser extent, higher oligomers of thehydrogenation product. Where isoprene is used, analysis by gaschromatography indicates, for example, the formation of isopentene aswell as of a mixture of various dimethyloctadienes and a smallproportion of higher oligomers.

Acyclic or cyclic dienes serve as suitable H acceptors, with 1,3-dienessuch as, for example, butadiene, isoprene or 1,3-cyclohexadiene beingpreferred. It has been found that 1-arylolefins, such as styrene,methylstyrene or 1,1-diphenylethene, do not produce satisfactory resultsin all cases. The use of 1-arylolefins as H acceptors is limited to thelithiation of relatively acidic five-membered heterocycles (such as, forexample, thiazole or other multiply heterosubstituted five-memberedrings). If 1-arylolefins are used for the metalation of less acidiccompounds such as, for example, thiophene or indole, the yields aredistinctly poorer than those obtained with the use of 1,3-dienes.

The H acceptor is used in a quantity of 0.2 to 3 mol, preferably 0.4 to1.5 mol, per mol of five-membered heterocycle. In most cases an Hacceptor in a quantity of 0.5 to 1.2 mol per mol of five-memberedheterocycle has proved advantageous.

The lithium metal used for the metalation should preferably be in finelydivided form, i.e. as powder having particle sizes of <0.1 mm. However,coarser forms, for example, granulated material having edge lengths ofseveral mm, may also be used. But the reaction times are then longer andthe reaction yields generally poorer, unless the coarsely granulatedlithium is used in excess. The lithium is typically used in a quantityof 0.5 to 3 mol, preferably 1 to 1.5 mol, per mol of five-memberedheterocycle. Where finely divided lithium is used, a largelystoichiometric quantity of 0.95 to 1.1 mol Li per mol of five-memberedheterocycle is sufficient.

The solvents used are open-chain or cyclic monethers, in particulartetrahydrofuran (THF) or methyl tert.-butyl ether (MTBE), or polyetherssuch as, for example, 1,2-dimethoxyethane (1,2-DME) or diethylene glycoldimethyl ether. These can be in pure form or mixed with one another ormixed with hydrocarbons such as, for example, pentane, hexane,cyclohexane, methylcyclohexane, heptane, octane, toluene orethylbenzene. As hydrocarbons are in general markedly less expensivethan ethereal solvents, a proportion of hydrocarbon in the solventsignifies an increase in the economic efficiency of the method accordingto the invention.

It has been observed that in a few instances, in particular in the caseof the less CH-acidic five-membered heterocycles such as, for example,2,3-dihydrofuran, the start of the reaction is delayed and/or itproduces only moderate yields. In these cases, in particular, it isadvisable to activate the metal by a known method. A particularlysuitable method for this is the addition of a metal phase transfercatalyst, referred to below as a phase transfer catalyst (PTC), such as,for example, naphthalene, anthracene, diphenyl ordi-tert.-butyldiphenyl. In anhydrous polar-aprotic solvents, theaforementioned polycyclic aromatics are able to add lithium with theformation of radical-anionic complexes. The oxide film on the metal isthereby broken up and lithium is converted into a highly reactive,soluble form. In this way the aforementioned catalysts lessen theunwanted induction phase; moreover, the result of their presence in thereaction mixture is that less H acceptor is required in order to achievea given product yield. The quantity of PTC added is typically 0 to 0.2mol, preferably 0 to 0.1 mol, per mol of five-membered heterocycle.

The experimental procedure is generally as follows:

First of all, the lithium metal is suspended in the anhydrous, aproticsolvent or mixture of solvents. The five-membered heterocycle to bemetalated is then added to the suspended metal. The reverse procedure(i.e. addition of the Li suspension or of the lithium to the solution ofthe five-membered heterocycle) is in principle also possible, but thisvariant has proved to be more complicated technically.

The metalation reaction is then initiated by adding the H acceptor.Where a phase transfer catalyst is used, it can be added in variousways. It is particularly advantageously added together with the lithium.It can also be introduced in a mixture with the H acceptor.

The most favourable reaction temperatures are generally between 0° C.and 60° C., with thermally labile solutions of the product beingobtained at lower temperatures. Higher temperatures tend to result indecomposition of the product; lower temperatures, owing to their higherenergy consumption, tend to be less economic.

The times taken to introduce the reagents are between about 15 minutesand several hours, depending on the five-membered heterocycle and on thecooling capacity. When the addition of the H acceptor is complete thereis a subsequent reaction stage, which generally takes 15 minutes to 4hours. On conclusion of the subsequent reaction, the reaction mixture isfiltered in order to remove unreacted metal and small quantities ofinsoluble secondary products.

The yields of selectively lithiated five-membered heterocycle which canbe attained by this method depend on the CH acidity and onreaction-specific variables (for example, type of solvent,stoichiometry, use of catalyst) and are between 30% and almost 100%.

A solution of the product containing approximately 5 to 25 wt. % of thelithiated five-membered heterocycle, hydrogenated dimers and oligomersof the H acceptor and optionally traces of the PTC is obtained.

It was observed that some of the solutions of the product preparedaccording to the invention, for example, 2-furanyllithium, in pureethereal solvents are insufficiently stable in storage. Whereas, forexample, an approximately 11 wt. % 2-furanyllithium solution having amolar ratio of 2-furanyl-Li:THF of approximately 1:7 at 25° C.decomposes at a rate of about 10% per day, the decomposition rate for asimilar 11 wt. % 2-furanyllithium solution in which a part of the THFhas been replaced by a hydrocarbon (for example, toluene or cyclohexane)and which has a molar ratio of 2-furanyl-Li:THF of approximately 1:1 isonly 0.12% per day. A solution of 2-furanyllithium which is low in THFis therefore far more stable and can be stored and transported for alonger period and without elaborate cooling methods.

The solutions of the final product such as, for example, 2-lithiofuran,referred to below as furanyllithium, or 2-lithiothiophene, referred tobelow as thienyllithium, can be derivatised by reaction withelectrophilic reagents such as, for example, carbonyl compounds,oxiranes, sulfur, carbon dioxide or alkyl halides. These products have avariety of uses in organic chemistry, in particular as intermediates forthe preparation of pharmaceuticals and plant protection products.

The subject matter of the invention is explained in more detail below bymeans of Examples.

EXAMPLES 1 TO 10

Examples 1 to 10 (shown in Table 2) demonstrate the preparation of2-thienyllithium from thiophene by means of different variants of themethod. Thiophene, with a pK_(a) value of 38.4, is only slightly moreacid than toluene (40.9). In Examples 1 to 5 and 7 to 10 the procedurewas in accordance with the following general operating instructions:

The lithium powder (particle size <0.1 mm) was suspended in the givensolvent and a phase transfer catalyst (PTC) was optionally addedthereto. After addition of 68 g (1.0 mol) of thiophene, the respective Hacceptor was added dropwise (styrene, isoprene) or passed in (butadiene)over a period of 1 to 2 hours. After a subsequent reaction time of 0.5to 4 hours, the reaction mixtures were clarified by filtration and theyield was determined by means of base titration or by means ofquantitative gas chromatography (GC). Here 2-trimethylsilylthiophene(after derivatisation of the product with trimethylchlorosilane) wasmeasured in the GC.

In Example 6 the procedure was similar. However, the phase transfercatalyst was not introduced beforehand in the solvent, but addedtogether with the H acceptor.

TABLE 2 Preparation of 2-thienyllithium Mol Molar ratio¹⁾ solvent Prepn.Yield (%) H PTC¹⁾³⁾ per mol temp.⁴⁾ Total Ex. Li acceptor²⁾ [mol %]thiophene [° C.] base⁵⁾ GC⁶⁾ 1 0.95 0.49 S / 3.0 THF ca. 25  5  3 2 0.990.49 S 6.9 N 3.0 THF ca. 25 73 47 3 1.1 0.58 I / 6.6 THF 25/50 56 61 40.97 0.61 I 1.0 N 6.9 THF ca. 23 70 73 5 0.97 0.62 I 3.1 N 6.9 THF ca.23 93 82 6 1.1 0.60 I 3.1 A 6.7 THF 25/50 65 61 7 0.97 0.63 I 2.9 N 2.0THF/ ca. 23 84 80 4.1 cyclohexane 8 0.97 0.75 I 2.0 N 2.0 THF/ 35 93 /3.1 toluene 9 0.96 0.59 I 3.0 N 5.3 1,2-DME ca. 23 78 / 10 0.94 1.0  B /2.0 THF/ ca. 10 87 90 2.8 toluene ¹⁾Thiophene = 1; ²⁾S = styrene; I =isoprene; B = 1,3-butadiene; ³⁾N = naphthalene; A = anthracene;⁴⁾Pre-/post reaction; ⁵⁾Total quantity of base in solution;⁶⁾Determination by gas chromatography as 2-trimethylsilylthiophene

The conclusions from Table 2 are as follows:

If styrene is used as H acceptor and the procedure is carried outwithout phase transfer catalyst (PTC), 2-thienyllithium is obtained onlyin very low yield (<5% Example 1). Under identical conditions, theaddition of 6.9 mol % naphthalene as PTC results in a marked increase inyield (Example 2). If isoprene is used instead of styrene, even withoutPTC a product yield of >50% is achieved (Example 3).

On the simultaneous addition of naphthalene as PTC, a further increasein yield is recorded (Examples 4 and 5). Other polycyclic aromatics, forexample, anthracene (Example 6), can also be used instead of naphthaleneas PTC.

The relatively costly THF can be partially replaced by cheaperhydrocarbons such as cyclohexane or toluene, without any observableadverse effect on the yield (Examples 7 and 8). But at least 2 mol of anethereal solvent, preferably THF, per mol of 2-thienyllithium should bepresent in the solution of the product, in order to obtain solutionswhich are non-crystallising.

Instead of being introduced beforehand, the PTC can also be addedtogether with the H acceptor (Example 8). Example 9 describes the use of1,2-dimethoxyethane as a reaction solvent. Example 10 shows that when alarger quantity of H acceptor is used (in this case, 1,3-butadiene),very good product yields can be achieved even without the use of PTC.

EXAMPLES 11 TO 16

Examples 11 to 16 (shown in Table 3) demonstrate the lithiation ofvarious five-membered heterocycles. Here the procedure was in accordancewith the following general operating instructions:

The lithium powder (particle size <0.1 mm) was suspended in the givensolvent, the phase transfer catalyst naphthalene was added thereto and,after the initial appearance of the green coloration, 0.5 mol of therespective CH-acidic five-membered heterocycle was added. The H acceptorisoprene was then added dropwise over a period of 1 to 2 hours. After asubsequent reaction time of approximately 1 hour, the reaction mixturewas clarified by filtration. The product, after derivatisation withmethyl iodide, was characterised by gas chromatography (GC) and massspectroscopy (MS) and the yield was determined by means of basetitration.

TABLE 3 Lithiation of various five-membered heterocycles Molar Het-ratio¹⁾ Solvent ero- Iso- PTC¹⁾²⁾ Mol/Mol Derivatisa- Yield Ex. cycle Liprene (mol %) heterocycle tion product³⁾ (%)⁴⁾ 11 0.91 0.66 3 0.9 THF/2-Me-furan 97 5.3 toluene 12 0.90 0.68 1 0.9 THF/ 2-Me-furan 65 5.9toluene 13 1.00 0.99 3 6.1 THF 2-Me- 60 dihydrofuran 14 0.95 0.98 2.95.5 1,2- 1,2-dimethyl- 82 DME pyrrole 15 1.00 1.03 3.2 12.0 THF1,2-dimethyl- 69 indole 16 1.00 0.51 2.9 8.7 THF / 86 ¹⁾Heterocycle = 1;²⁾PTC = naphthalene ³⁾Reaction with methyl iodide and identification byGC/MS; ⁴⁾Determination of the alkalinity of the solution by filtration

The conclusions from Table 3 are as follows:

Furan can be lithiated with very good yields, and naphthalene promotesproduct formation (Examples 11 and 12). The less acidic 2,3-dihydrofuranproduces smaller yields, although more H acceptor was used (Example 13).N-methylpyrrole in 1,2-dimethoxyethane reacts to produce2-lithio-N-methylpyrrole in good yields (Example 14).

N-methylindole is lithiated in THF with satisfactory yields (Example15). Even a small quantity of hydrogen acceptor suffices for thelithiation of the relatively acidic 4-methylthiazole (Example 16).

What is claimed is:
 1. Method of lithiating CH-acidic five-memberedheterocycles, wherein the five-membered heterocycle is reacted withmetallic lithium in an ether-containing solvent in the presence of an Hacceptor, and the CH-acidic bond of the five-membered heterocycle has apK_(a) value of 30 to 40 and the H acceptor is an open-chain,unsubstituted or substituted

wherein R¹, R² =H, alkyl, vinyl, wherein R¹, R² in cis or transconfiguration or a cyclic 1,3-diene

wherein n=1 to 5 and is used in a quantity of 0.2 mol to 3 mol per molof five-membered heterocycle.
 2. Method of lithiating CH-acidicsubstituted five-membered heterocycles, wherein the five-memberedheterocycle is reacted with metallic lithium in an ether-containingsolvent in the presence of an H acceptor, and the CH-acidic bond of thefive-membered heterocycle has a pK_(a) value of 30 to 40 and the Hacceptor is an open-chain, unsubstituted or substituted 1,3-diene, or acyclic 1,3-diene, or an unsubstituted or substituted 1-arylolefin

wherein R³, R⁴=H, alkyl of 1 to 5 C atoms wherein R³, R⁴ in cis or transconfiguration and is used in a quantity of 0.2 mol to 3 mol per mol offive-membered heterocycle.
 3. The method of claim 1 wherein thefive-membered heterocycle includes at least one ring hetero atomselected from the group consisting of O, S, N or Se and at least oneCH-acidic group in the α-position to said hetero atom and wherein the Catom of the CH-acidic group is sp-hybridized.
 4. The method of claim 1wherein the five-membered heterocycle is furan, 2,3-dihydrofuran,thiophene or pyrrole and wherein the five-membered heterocycle issubstituted or unsubstituted, and wherein the five membered heterocycleincludes an unsubstituted CH-acidic group situated in the α-position toa ring hetero atom.
 5. The method of claim 1 wherein the H acceptor isisoprene, butadiene or 1,3-cyclohexadiene.
 6. The method of claim 1wherein the H acceptor is used in a quantity of 0.4 to 1.5 mol per molof the five-membered heterocycle.
 7. The method of claim 1 wherein thelithium metal is used in finely divided form, as powder having particlesizes of <0.1 mm.
 8. The method of claim 1 wherein the solvent comprisesone or more open-chain or cyclic ethers, or mixtures of one or moreethers and of one or more hydrocarbons.
 9. The method of claim 8 whereinthe solvent is THF in pure form or mixed with hydrocarbons.
 10. Themethod of claim 9 wherein the hydrocarbon is pentane, hexane,cyclohexane, methylcyclohexane, heptane, octane, toluene orethylbenzene.
 11. The method of claim 1 wherein the reaction is carriedout in the presence of a metal phase transfer catalyst, the metal phasetransfer catalyst being used in a quantity of up to 0.2 mol per mol offive-membered heterocycle.
 12. The method of claim 11 wherein the metalphase transfer catalyst is a polycyclic aromatic.
 13. The method ofclaim 12 wherein the polycyclic aromatic is naphthalene, anthracene,diphenyl or di-tert.-butyldiphenyl.